American Journal Of Physiology. Cell Physiology[JOURNAL]
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200 papers
ADAM17-induced shedding of glypican-1 as a mechanism of impaired endothelial shear stress mechanotransduction.
Augenreich MA, Ferreira-Santos L, Power G … +9 more , Ramirez-Perez FI, Gonzalez-Vallejo JD, Williams MB, Imkaew N, Cho MJ, Wheeler AA, Manrique-Acevedo C, Martinez-Lemus LA, Padilla J
Am J Physiol Cell Physiol · 2026 Mar · PMID 41544633 · Full text
Endothelial dysfunction occurs early in the pathogenesis of type 2 diabetes (T2D)-associated cardiovascular disease. Previous work has revealed that endothelial glycocalyx mechanosensing structures are degraded in T2D, l...
Endothelial dysfunction occurs early in the pathogenesis of type 2 diabetes (T2D)-associated cardiovascular disease. Previous work has revealed that endothelial glycocalyx mechanosensing structures are degraded in T2D, likely contributing to impaired shear stress mechanotransduction and consequent blunted vasodilation. Evidence from proteomic analysis suggests that glypican-1, a well-known mechanosensor, is a substrate of the proinflammatory enzyme ADAM17. A critical step in ADAM17 activation is externalization of phosphatidylserine (PS) to the outer leaflet of the plasmalemma, which can be enacted by the Ca-activated phospholipid scramblase anoctamin-6 (ANO6). However, whether ANO6-mediated activation of ADAM17 leads to glypican-1 shedding in endothelial cells remains unknown. Also, unknown are the mechanisms by which this pathway becomes overactive in T2D. We recently reported that the activity of neuraminidase, a soluble enzyme that cleaves sialic acid, is elevated in the plasma of individuals with T2D and that this occurs in concert with increased ADAM17 activity. Here, in an extended cohort of males and females with T2D, we report that this association is also coupled with reduced flow-mediated dilation (FMD). Furthermore, we report that subjecting endothelial cells to neuraminidase increases intracellular Ca, which provokes ANO6-mediated PS externalization, leading to ADAM17-dependent reductions of glypican-1. In isolated arteries, intraluminal exposure to neuraminidase impairs FMD, which can be prevented by ANO6 or ADAM17 inhibition. Lastly, isolated arteries from endothelial cell-specific ADAM17 knockout mice fed a Western diet exhibit greater FMD than genetic controls. Collectively, this work identifies the neuraminidase-ANO6-ADAM17 axis as a potential novel mechanism underlying impaired endothelial shear stress mechanotransduction in T2D. We provide evidence that neuraminidase, which is elevated in plasma from males and females with type 2 diabetes (T2D), is involved in the activation of endothelial ADAM17 and shedding of the mechanosensor glypican-1. We also provide evidence that neuraminidase-induced ADAM17 activation and consequent glypican-1 shedding are mediated by ANO6 scramblase externalization of phosphatidylserine. Together, this work suggests the neuraminidase-ANO6-ADAM17 axis may be a mechanism underlying impaired endothelial shear stress mechanotransduction in T2D.
Lyophilized mesenchymal stem cell-derived extracellular vesicles improve outcomes in acute liver failure models.
Suzuki F, Haga H, Inuzuka T … +5 more , Hoshikawa K, Katsumi T, Maki K, Uchiyama F, Ueno Y
Am J Physiol Cell Physiol · 2026 Feb · PMID 41543349 · Publisher ↗
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are promising for the treatment of liver diseases, including acute liver failure (ALF). However, efficient preservation methods suitable for clinical use rem...
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are promising for the treatment of liver diseases, including acute liver failure (ALF). However, efficient preservation methods suitable for clinical use remain under investigation. In this study, we evaluated the preservation efficacy and therapeutic effects of lyophilized MSC-EVs in a mouse model of ALF. EVs were isolated from bone marrow-derived MSCs and allocated to four preservation conditions: nonlyophilized (fresh), phosphate-buffered saline (PBS), 1% sucrose, and 5% sucrose. EVs were characterized by nanoparticle tracking analysis, Bioanalyzer, absorbance measurements, RNA sequencing, and transmission electron microscopy (TEM). ALF was induced by d-galactosamine and TNF-α, and mice were treated with PBS, empty EVs (m-Encapsome), nonlyophilized EVs, or lyophilized EVs (5% sucrose). Among the preservation conditions, the 5% sucrose group retained the highest EV yield, exhibited a unimodal particle size distribution, and preserved EV morphology, whereas the PBS and 1% sucrose groups showed structural damage and multimodal particle size distributions. Total RNA and protein levels were comparable among groups; however, miRNA sequencing demonstrated a strong correlation between nonlyophilized EVs and 5% sucrose-lyophilized EVs. In the ALF model, 5% sucrose-lyophilized EVs significantly reduced serum alanine transaminase (ALT) levels, inflammatory cytokines, hepatocyte necrosis, TUNEL-positive cells, PCNA-positive cells, and Ki-67-positive cells, with effects comparable to those of nonlyophilized EVs. These findings demonstrate that lyophilization with 5% sucrose effectively preserves MSC-EV integrity and therapeutic potential, supporting future clinical applications of MSC-EVs for liver disease treatment. This study establishes lyophilization with 5% sucrose as an effective preservation method for mesenchymal stem cell-derived extracellular vesicles (MSC-EVs). Preserved EVs maintained structural integrity and miRNA profiles comparable to fresh EVs. In a mouse model of acute liver failure, they demonstrated equivalent therapeutic efficacy. These findings overcome storage limitations, facilitating the clinical translation of MSC-EVs as a stable treatment for liver diseases.
Orai channels in proliferation, invasion, and chemoresistance of tumor cells.
Jardín I, Macias-Díaz A, Jimenez-Velarde V … +2 more , Smani T, Rosado JA
Am J Physiol Cell Physiol · 2026 Feb · PMID 41543347 · Publisher ↗
Calcium signaling via store-operated calcium entry (SOCE) is critical for cellular functions implicated in cancer progression. Alterations in Orai channel isoforms, particularly Orai1 and Orai3, modulate SOCE and influen...
Calcium signaling via store-operated calcium entry (SOCE) is critical for cellular functions implicated in cancer progression. Alterations in Orai channel isoforms, particularly Orai1 and Orai3, modulate SOCE and influence tumor cell proliferation, invasion, and survival. Here, we review and synthesize current evidence showing how Orai1 and Orai3 isoforms modulate oncogenic calcium signals through pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt, ERK1/2, and NF-κB, contributing to tumor progression and chemoresistance by regulating apoptosis, autophagy, and oxidative stress responses. This isoform-specific remodeling enables tumor cells to adapt to therapeutic challenges and oxidative environments. Emerging data suggest that modulating Orai channel function and isoform composition may sensitize some cancer cells to apoptosis and attenuate invasive behavior, at least in specific experimental models. Taken together, available studies support a role for Orai channels as important regulators of tumor-associated Ca signaling and highlight their potential as context-dependent targets to modulate survival and invasive behavior in cancer models.
Understanding the effect of estrogen on B cells: implications for immune health and autoimmunity.
Gunduz H, Sun A, Diamond B
Am J Physiol Cell Physiol · 2026 Feb · PMID 41533344 · Full text
Estrogen is a steroid hormone involved in the regulation of multiple systems in the body. Among these, the immune system is of particular interest due to the significant female predominance seen in many autoimmune diseas...
Estrogen is a steroid hormone involved in the regulation of multiple systems in the body. Among these, the immune system is of particular interest due to the significant female predominance seen in many autoimmune diseases. Since B cells and B-cell-driven antibody responses are central to the development of autoimmune diseases, the influence of estrogen on B cells has been extensively investigated. Throughout B-cell development, estrogen exerts complex and contrasting effects depending on the level of exposure to estrogen and the stage of development of the B cell. For instance, at early stages, high concentrations of estrogen negatively regulate early B-cell precursor development, whereas low baseline concentrations are stimulatory and essential. Conversely, estrogen exposure at later stages leads to increased rescue of autoreactive B cells, enabling their maturation and subsequent autoantibody production, a mechanism that contributes to the development of a systemic lupus erythematosus-like phenotype in murine models. Beyond rescuing autoreactive cells, estrogen can also modulate the function of germinal centers, where autoreactive antibodies may arise through somatic hypermutation. The complex interplay of these effects sets the stage for both the heightened immune response and increased autoimmunity observed in females. In this review, we will explore the various effects of estrogen on B cells to provide a comprehensive overview of the role of estrogen in shaping immune function and enhancing autoimmunity.
The role of osteomimicry factors in prostate cancer progression and metastasis.
Elshafae SM, Utzman PH, Moussa MA … +3 more , Fotouh A, Ponnazhagan S, Hildreth BE
Am J Physiol Cell Physiol · 2026 Mar · PMID 41533336 · Publisher ↗
Prostate cancer progression and metastasis are complex steps that are controlled by various molecular and cellular mechanisms. Here, the process of osteomimicry has a vital role in the context of bone metastasis. Osteomi...
Prostate cancer progression and metastasis are complex steps that are controlled by various molecular and cellular mechanisms. Here, the process of osteomimicry has a vital role in the context of bone metastasis. Osteomimicry phenomenon refers to the ability of cancer cells to acquire bone-like properties, thus enabling them to adapt to and survive in their bone microenvironment. This phenomenon promotes cancer cell and bone microenvironment interactions and contributes directly to tumor survival, growth, and the development of bone metastatic lesions. In this review, we discuss the role of different osteomimicry factors in prostate cancer progression and metastasis, highlighting their involvement in each stage of the metastatic cascade. Key factors involved in osteomimicry-such as bone matrix proteins, signaling pathways, and transcriptional regulators-play important roles throughout the various stages of cancer progression. These include the initial development of the tumor, its local invasion into surrounding tissues, entry into the bloodstream (intravasation), spread to other more distant areas (extravasation), and ultimately, colonization and growth in the bone. Gaining a better understanding of how these factors are regulated, interact, and function can shed light on new treatment strategies aimed at targeting osteomimicry to slow down or prevent the progression of prostate cancer and its spread to the bones.
Targeting activated kidney fibroblasts via ferroptosis: a potential antifibrotic strategy.
Sörensen-Zender I, Song R, Sinning J … +4 more , Kapanadze T, Schmidt-Ott KM, Melk A, Schmitt R
Am J Physiol Cell Physiol · 2026 Mar · PMID 41533090 · Publisher ↗
Kidney fibrosis is characterized by excessive deposition of extracellular matrix, which is ultimately disrupting normal renal architecture. Despite its clinical relevance, no targeted antifibrotic therapies are currently...
Kidney fibrosis is characterized by excessive deposition of extracellular matrix, which is ultimately disrupting normal renal architecture. Despite its clinical relevance, no targeted antifibrotic therapies are currently available. Myofibroblasts, primarily derived from pericytes and resident fibroblasts, are key effectors of fibrosis due to their high extracellular matrix production. Here, we tested the hypothesis that ferroptosis induction would enable the targeted elimination of activated kidney fibroblasts. We found that kidney fibroblasts exhibit marked sensitivity to ferroptotic cell death upon exposure to the ferroptosis inducer RAS-selective lethal 3 (RSL3), an effect further amplified by transforming growth factor-β stimulation. In tissue slice cultures of murine fibrotic kidneys, RSL3 eliminated myofibroblasts without causing overt damage to other cell types. Extending these findings in vivo, we applied a postischemia/reperfusion model of kidney fibrosis and demonstrated that repeated low-dose systemic administration of RSL3 significantly reduced the activated fibroblast population without inducing appreciable injury to parenchymal cells. These results provide proof-of-principle that the ferroptosis susceptibility of activated fibroblasts may offer a potential strategy for the selective depletion of profibrotic effector cells in kidney fibrosis. This study reveals ferroptosis, a pharmacologically inducible form of cell death, as a novel mechanism to eliminate activated fibroblasts, the main drivers of kidney fibrosis. Due to their high ferroptosis sensitivity, these cells are selectively depleted by RSL3 in vitro, in kidney tissue slice cultures, and in fibrotic kidneys in vivo. These findings highlight ferroptosis induction as a promising antifibrotic strategy in kidney disease.
PLGA nanoparticles restore acidic pH and degradative function to compromised lysosomes with Cy3-labeling providing enhanced tracking to lysosomes.
Li J, Wang T, Lu W … +9 more , Jishkariani D, Tsourkas A, Kaja S, Vining KH, Thussananutiyakul J, Spence A, Nair RM, Dunaief JL, Mitchell CH
Am J Physiol Cell Physiol · 2026 Feb · PMID 41533007 · Full text
Lysosomal dysfunction and elevated lysosomal pH are hallmark features of age-related neurodegenerative diseases including age-related macular degeneration (AMD), Alzheimer's disease (AD), and Parkinson's disease (PD). Re...
Lysosomal dysfunction and elevated lysosomal pH are hallmark features of age-related neurodegenerative diseases including age-related macular degeneration (AMD), Alzheimer's disease (AD), and Parkinson's disease (PD). Restoring lysosomal acidity is important for maintaining enzymatic degradation, preventing protein aggregation, and reducing cellular waste accumulation in degenerating tissues. Acidic nanoparticles represent a promising therapeutic strategy to normalize lysosomal pH; however, accurate monitoring of their delivery, retention, and dosage is critical for rigorous evaluation. To address this, we developed fluorescently labeled poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles conjugated with Cyanine3 amine (Cy3). Nanoparticle uptake was systematically optimized, achieving over 90% delivery to lysosomes of induced pluripotent stem cell-derived retinal pigment epithelial (iPS-RPE) cells, although uptake rates varied among adjacent cells. Once internalized, nanoparticles demonstrated remarkable stability, with no detectable change in concentration, distribution, or size for at least 28 days. iPS-RPE cells exhibited higher nanoparticle internalization compared with the ARPE-19 cell line and optic nerve head astrocytes. The capacity of the nanoparticles to restore function to stressed lysosomes was confirmed by their ability to reacidify lysosomes, restore cathepsin B activity, and increase the levels of active cathepsin D. The nanoparticles also reduced the levels of LC3II in astrocytes treated with chloroquine, indicating that they can also restore autophagy rates. In summary, this study demonstrates the value of Cy3 labeling for enhanced nanoparticle tracking to lysosomes. The findings also identify PLGA nanoparticles as powerful tools for restoring degradative lysosomal function and autophagy in cells undergoing lysosomal stress. Tools that restore acidic pH in compromised lysosomes can enhance autophagy and waste clearance in degenerative disorders characterized by excessive accumulation. Here, we describe the synthesis of lysosome-targeted nanoparticles composed of poly(d,l-lactide-co-glycolide) (PLGA) polymers covalently bound to the fluorescent dye Cyanine3 amine (Cy3). These Cy3-PLGA nanoparticles enable precise tracking of lysosomal delivery and demonstrate sustained long-term retention within lysosomes, supporting their potential for future applications aimed at restoring lysosomal pH in aging and degenerating diseases.
Differentiating between BK activation and potentiation by vanzacaftor enantiomers.
Baumlin N, Horrigan FT, Bossmann SH … +1 more , Salathe M
Am J Physiol Cell Physiol · 2026 Feb · PMID 41525766 · Publisher ↗
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Central activation of chaperone-mediated autophagy reduces appetite by fine-tuning hypothalamic amino acid pools: new insights from fish.
Reji S, Vélez EJ, Blanco AM … +11 more , Heraud C, Véron V, Dias K, Stella A, Burlet-Schiltz O, Schnebert S, Roy J, Beaumatin F, Cleveland B, Soengas JL, Seiliez I
Am J Physiol Cell Physiol · 2026 Mar · PMID 41525106 · Publisher ↗
Chaperone-mediated autophagy (CMA) is a key lysosomal proteolytic pathway essential for cellular homeostasis and metabolism, with dysfunction linked to various human diseases. Although extensively studied in humans and m...
Chaperone-mediated autophagy (CMA) is a key lysosomal proteolytic pathway essential for cellular homeostasis and metabolism, with dysfunction linked to various human diseases. Although extensively studied in humans and mice, CMA was only recently identified in fish, paving the way for novel and evolutionary research perspectives. Here, we demonstrate a role for CMA in regulating feed intake (FI) in rainbow trout (), a major aquaculture species and a widely used model in numerous research fields, including physiology, evolutionary genetics, toxicology, immunology, and nutrition. Specifically, we observed that feed deprivation induces an increase in the CMA activation score-a reliable proxy for CMA activity-in the hypothalamus, a central brain region involved in the regulation of feeding behavior. To probe its functional relevance, we intracerebroventricularly (ICV) injected the CMA activator CA77.1 and found a significant reduction in FI levels, suggesting a regulatory role for CMA in appetite. Further analysis suggested that CMA may regulate FI partly through changes in hypothalamic free amino acid availability, with ribosomal protein degradation potentially contributing to this mechanism. Through this mechanism, CMA may play a critical role in the precise regulation of satiety and also represent a promising target for therapeutic strategies aimed at treating metabolic disorders, as well as for nutritional interventions to improve feed efficiency and promote more sustainable growth practices in aquaculture. This study shows in vivo, in a nonmammalian vertebrate, that chaperone-mediated autophagy (CMA) regulates appetite. It demonstrates that hypothalamic CMA activity increases during feed deprivation and that pharmacological activation of CMA suppresses feed intake by locally modulating amino acid availability. These findings reveal a previously uncharacterized link between CMA, hypothalamic amino acid pools, and appetite regulation, and suggest a novel intracellular mechanism linking proteostasis to nutrient sensing and feeding behavior in vertebrates.
Ablation of tumor-derived IGFBP-3 attenuates cancer-associated skeletal muscle wasting in murine pancreatic cancer.
Sechrist ZR, Belcher DJ, Patel NR … +3 more , Pittman ZJ, Schwarz EM, Cole CL
Am J Physiol Cell Physiol · 2026 Feb · PMID 41525104 · Full text
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths, and its incidence is expected to rise. Skeletal muscle wasting (SMW) is a debilitating comorbidity of PDAC with unknown etiolo...
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths, and its incidence is expected to rise. Skeletal muscle wasting (SMW) is a debilitating comorbidity of PDAC with unknown etiology. Previously, our lab demonstrated that systemic increases in insulin-like growth factor-binding protein-3 (IGFBP-3) are associated with SMW and pathologic myocellular lipid accumulation in an orthotopic murine model of PDAC [;; (KCKO)]. Here we show that PDAC tumor cells secrete high levels of IGFBP-3 and that genetic ablation of IGFBP-3 (IGFBP-3) in the KCKO and ;; (KP2) orthotopic models of PDAC increases survival by at least 30 days in both models without affecting tumor progression. Mice with tumors lost 10- and 3-fold less appendicular lean mass, and experienced a five- and sixfold decrease in myocellular lipid accumulation versus mice with parental KCKO and KP2 tumors, respectively, at failure to thrive endpoints. Gene expression studies demonstrated increases in the ubiquitin-proteasome pathway ( and ), autophagy (ULK1 and LC3bII), and transforming growth factor-β receptor (TGF-βR) signaling ( and FoxO1) in skeletal muscle of mice inoculated with parental PDAC tumors, which was absent in mice with tumors. In vitro studies confirmed a role for IGFBP-3 in stimulating TGF-β receptors and regulating SMAD3 nuclear localization. Moreover, IGFBP-3 deletion in tumor cells and small molecule inhibition of TGF-βR1/2 attenuated myotube wasting. Collectively, these results suggest that PDAC-derived IGFBP-3 promotes SMW via noncanonical binding of TGF-βRs, warranting formal investigation of IGFBP-3 as a potential therapeutic target for PDAC-related SMW through a novel pathway. The mechanism underlying PDAC-associated SMW is not well understood but has been connected to increases in systemic IGFBP-3 to supraphysiologic levels, resulting in dysregulated protein synthesis and catabolism signaling. Here, we show that genetic deletion of IGFBP-3 in orthotopic PDAC tumors significantly improves survival and muscle phenotypes in mice. Molecular studies suggest the role for noncanonical IGFBP-3 signaling through TGF-β receptors. Thus, IGFBP-3 may be a therapeutic target in the treatment of PDAC-related SMW.
Loss of α7 nicotinic acetylcholine receptor exacerbates adrenergic-induced cardiac damage.
Miranda K, Teixeira VP, Scalzo SA … +12 more , Estevão LRM, Santos AK, Sanches B, Eliezeck M, Espanhol FA, Abramo H, Kangussu LM, Barcelos LS, Prado V, Prado MAM, Rocha-Resende C, Guatimosim S
Am J Physiol Cell Physiol · 2026 Mar · PMID 41524132 · Publisher ↗
Previous studies have implicated the α7 nicotinic acetylcholine receptor (α7nAChR) in cardioprotection via its anti-inflammatory effects, yet the underlying mechanisms remain poorly understood. Here, we investigated the...
Previous studies have implicated the α7 nicotinic acetylcholine receptor (α7nAChR) in cardioprotection via its anti-inflammatory effects, yet the underlying mechanisms remain poorly understood. Here, we investigated the impact of α7nAChR deficiency on cardiac injury induced by a 7-day isoproterenol (ISO) treatment in littermate wild-type (WT) and α7nAChR-knockout (α7-KO) mice. ISO administration in WT mice led to a marked upregulation of α7nAChR expression in cardiac tissue and isolated cardiomyocytes, suggesting a compensatory response to adrenergic stress. To investigate this hypothesis, we assessed ISO-induced structural and inflammatory changes in both genotypes. ISO-treated WT mice developed isolated cardiac hypertrophy with minimal inflammation or fibrosis. In contrast, α7-KO mice subjected to ISO treatment displayed exacerbated hypertrophy and fibrosis. These alterations were accompanied by marked leukocyte accumulation, supporting the anti-inflammatory role of α7nAChR. To explore this further, we characterized the inflammatory profile using flow cytometry. FACS-analyzed hearts from α7-KO/ISO mice exhibited increased monocyte infiltration and a marked expansion of the CCR2 population compared with WT/ISO. This phenotype was associated with greater cardiomyocyte death. In vitro, isolated ventricular myocytes lacking α7nAChR were intrinsically more susceptible to ISO-induced cytotoxicity, indicating that α7nAChR exerts a cell-autonomous protective role beyond its anti-inflammatory function. Our findings establish α7nAChR as a key determinant of cardiac resilience to adrenergic insult and underscore its potential as a therapeutic target for mitigating myocardial injury. Although α7nAChR has been implicated in cardioprotection through its anti-inflammatory properties, the mechanisms underlying these effects remain elusive. We demonstrate that α7nAChR deficiency heightens susceptibility to adrenergic-induced injury, characterized by enhanced cardiomyocyte death and monocyte infiltration. Our findings confirm the anti-inflammatory role of α7nAChR and reveal its cell-autonomous prosurvival effects on cardiomyocytes, broadening our understanding of mechanisms driving cholinergic cardioprotection. This work positions α7nAChR as a regulator of myocardial resilience and highlights its therapeutic potential.
Postnatal development and form-function relationships of the vocal folds in California mice ().
Miller A, Sherwood M, Titze IR … +2 more , Bussey KJ, Riede T
Am J Physiol Cell Physiol · 2026 Feb · PMID 41512279 · Full text
Most mammals produce vocal signals through vocal fold oscillations in the larynx, driven by airflow. Common species used as models (e.g., house mice, rats, and rabbits) may not reflect the cellular specializations or dev...
Most mammals produce vocal signals through vocal fold oscillations in the larynx, driven by airflow. Common species used as models (e.g., house mice, rats, and rabbits) may not reflect the cellular specializations or developmental adaptations needed to support diverse vocal strategies or tissue repair under the mechanical stresses of phonation in humans. This study investigates vocal fold structure and function in California mice () to inform a new model of vocal fold biomechanics. These mice can produce extremely high fundamental frequencies () via airflow-induced vocal fold vibration and maintain this ability throughout life. We examined how vocal fold structure relates to function in California mice across three developmental stages. Vocal folds grow with negative allometry, undergoing changes in shape and composition. The epithelium is made up of 1-2 layers of squamous cells, and the lamina propria contains a fibrous matrix rich in collagen and hyaluronan but low in elastin. In vitro, California mouse vocal fold fibroblasts differed from those of house mice () in size, shape, and α-smooth muscle actin expression. In addition, intrinsic laryngeal muscle myofibers doubled in diameter during the first 3 wk of life. We propose that the differentiated allometric growth of the larynx and vocal folds helps stabilize across development. A species-specific fibroblast phenotype may support vibration and enhance tissue resilience. These findings suggest that cellular adaptations in the vocal folds may play a larger role in species-specific vocal function and stability than previously recognized. California mice produce high-pitched vocalizations through specialized vocal fold structures that grow and develop uniquely across life stages. Unlike common lab species, their vocal folds show distinct cellular traits that support vibration and durability. This study highlights key differences in tissue composition and fibroblast behavior, suggesting that species-specific vocal fold adaptations may be crucial for stable vocal function-offering new insights into voice biomechanics and potential models for human vocal health research.
STL1267 inhibits myofibroblast differentiation in a TGFβ1-driven human lung fibroblast model.
Prasad C, Huang SK, Burris TP … +1 more , Sundar IK
Am J Physiol Cell Physiol · 2026 Mar · PMID 41512274 · Full text
Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive fibroblast-to-myofibroblast transition (FMT) and extracellular matrix (ECM) deposition, largely driven by transforming growth facto...
Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive fibroblast-to-myofibroblast transition (FMT) and extracellular matrix (ECM) deposition, largely driven by transforming growth factor-beta 1 (TGFβ1). Existing therapies offer limited efficacy, particularly in advanced disease. Circadian rhythms have recently emerged as key modulators of lung inflammation and fibrosis. In this study, we developed an in vitro model of chronic fibrotic signaling using adenovirus-mediated TGFβ1 overexpression (Ad-TGFβ1) or human recombinant protein TGFβ1 in primary normal human lung fibroblasts. Using this model, we investigated the antifibrotic potential of STL1267, a next-generation REV-ERBα agonist with improved potency, specificity, and pharmacokinetic properties. RNA sequencing and pathway analysis revealed that STL1267 significantly reversed Ad-TGFβ1-induced expression of genes associated with ECM remodeling, collagen biosynthesis, and immune suppression. STL1267 also upregulated pathways related to IL-10, IL-4, and IL-13 signaling, which are known to counteract fibrotic responses. Quantitative PCR and immunoblotting confirmed STL1267's ability to downregulate key profibrotic markers, including COL1A1, αSMA, FN1, and FAP, at both gene and protein levels. Comparative studies with other Rev-erbα agonists (GSK4112, SR9009), saracatinib, and Food and Drug Administration (FDA)-approved antifibrotic drugs (pirfenidone, nintedanib) demonstrated superior efficacy of STL1267 in inhibiting both preventive and postfibrotic induction models. Moreover, lentiviral overexpression of Rev-erbα suppressed TGFβ1-induced αSMA expression, supporting a direct antifibrotic role. These findings highlight Rev-erbα as a key regulator of myofibroblast differentiation and support both STL1267 and GSK4112 as promising candidates for circadian-based antifibrotic therapy. Future in vivo studies are warranted to evaluate its translational potential in idiopathic pulmonary fibrosis. This study introduces a novel in vitro adenovirus-based model of persistent TGFβ1 signaling in normal human lung fibroblasts to mimic chronic fibrosis. Using this model, we show that the next-generation REV-ERBα agonist STL1267 robustly inhibits myofibroblast differentiation and ECM gene expression. STL1267 outperforms Food and Drug Administration-approved antifibrotic drugs and modulates immune and circadian signaling pathways, supporting its potential as a promising circadian-based therapeutic strategy for pulmonary fibrosis.
GPR39 activation inhibits AQP2 trafficking and alters cytoskeletal organization.
Kui MK, Zhang JJ, Ahmed IA … +4 more , Patel SK, Fallah Rastegar T, Rabb H, Pluznick JL
Am J Physiol Cell Physiol · 2026 Feb · PMID 41494658 · Full text
G protein-coupled receptor 39 (GPR39) is an orphan receptor that is highly expressed in renal collecting duct principal cells. GPR39 activation in vivo leads to reduced urinary concentration capacity. In this study, we u...
G protein-coupled receptor 39 (GPR39) is an orphan receptor that is highly expressed in renal collecting duct principal cells. GPR39 activation in vivo leads to reduced urinary concentration capacity. In this study, we used mpkCCD cells, a model of principal cells in the collecting duct, to examine the cell biological effects of GPR39 activation. Pharmacological activation of GPR39 with the synthetic agonist cpd1324 impaired vasopressin-mediated aquaporin-2 (AQP2) apical trafficking and reduced total AQP2 expression following long-term treatment, consistent with its known in vivo role. These effects were absent in GPR39 knockout cells. In addition, GPR39 activation altered apical membrane morphology, disrupted the tight junction network, and reduced cortical F-actin expression, suggesting a shift toward a dedifferentiated phenotype. GPR39 activation also increased glycolytic ATP production while reducing mitochondrial ATP output without affecting proliferation. RNA-Seq analysis of acutely treated mpkCCD cells revealed upregulation of inflammatory and dedifferentiation-associated gene programs, including cytokines. These findings indicate that the role of GPR39 in principal cells goes beyond AQP2 regulation and imply that GPR39 functions as a negative regulator of epithelial differentiation, perhaps acting to coordinate metabolic and inflammatory responses to stress. This study presents the first exploration of the cellular and molecular mechanisms underlying GPR39 activation in a physiologically relevant in vitro model of the renal collecting duct, mpkCCD cells. Our findings implicate GPR39 in the regulation of aquaporin-2 expression and trafficking, cytoskeletal organization, and cellular metabolism. In addition, RNA sequencing of GPR39-activated cells revealed transcriptomic changes related to immune signaling, stress response, and differentiation.
A hepatocyte membrane-based culture system recapitulating the physiological microenvironment of hepatic stellate cells.
Inoue K, Matsubara T, Urushima H … +7 more , Yuasa H, Daikoku A, Ikeda K, Kawada N, Yoshizato K, Suzuki T, Sato-Matsubara M
Am J Physiol Cell Physiol · 2026 Feb · PMID 41494642 · Publisher ↗
Liver fibrosis is a progressive disease primarily driven by the activation of hepatic stellate cells (HSCs). Understanding the mechanisms regulating HSC activation requires an in vitro model that accurately recapitulates...
Liver fibrosis is a progressive disease primarily driven by the activation of hepatic stellate cells (HSCs). Understanding the mechanisms regulating HSC activation requires an in vitro model that accurately recapitulates the hepatic microenvironment. In vivo, quiescent HSCs form direct contact with hepatocytes (Heps) through fine dendritic processes known as spines, which are essential for maintaining liver architecture and homeostasis. However, conventional extracellular matrix-based culture systems fail to reproduce these physiological cell-cell interactions. In this study, we aimed to establish a novel HSC culture platform using Heps plasma membrane (Hep-PM) as a substrate to mimic direct Heps-HSCs adhesion. Primary mouse and human HSCs cultured on Hep-PM retained dendritic, star-like morphologies characteristic of quiescent cells and exhibited markedly reduced expression of alpha-smooth muscle actin (α-SMA) and collagen type I alpha 1, key markers of HSC activation. Remarkably, Hep-PM also promoted the deactivation of activated HSCs, suggesting that both activation and reversion processes can be recapitulated in vitro. Furthermore, HSCs maintained on Hep-PM remained responsive to transforming growth factor β (TGF-β), indicating that quiescence was preserved without loss of activation potential. This system recreates the hepatic microenvironment, enabling dynamic and quantitative evaluation of HSC phenotypes. The Hep-PM platform offers a powerful tool for elucidating HSC regulatory mechanisms and screening antifibrotic compounds and may ultimately inform the design of Heps-mimetic therapeutics for liver fibrosis. We developed a hepatocyte plasma membrane-based culture system that mimics in vivo cell-cell adhesion to regulate hepatic stellate cell (HSC) phenotypes. This platform maintains HSC quiescence by reducing activation markers and preserving a quiescent morphology, while allowing the observation of HSC activation in response to TGF-β treatment. It provides a physiologically relevant tool for studying HSC regulation and screening antifibrotic therapies, advancing in vitro modeling of liver fibrosis.
Cystamine is a redox-dependent inverse agonist of the histamine H receptor.
Honda T, Sakaguchi T, Kuramasu A
Am J Physiol Cell Physiol · 2026 Feb · PMID 41481277 · Publisher ↗
Cystamine, the oxidized dimer of cysteamine, has been reported to exert anti-inflammatory actions, but the underlying molecular mechanism remains unclear. Because the histamine H receptor (H4R) is a key regulator of mast...
Cystamine, the oxidized dimer of cysteamine, has been reported to exert anti-inflammatory actions, but the underlying molecular mechanism remains unclear. Because the histamine H receptor (H4R) is a key regulator of mast cell chemotaxis and inflammatory signaling, we examined whether cystamine directly modulates H4R activity. Cystamine potently inhibited histamine-induced mast cell migration (IC = 440 nM) without affecting stem cell factor-induced migration, indicating pathway specificity. Although cystamine suppressed transglutaminase activity, this required millimolar concentrations and did not account for its effect on migration. At low micromolar concentrations, cystamine attenuated histamine-dependent activation of Rac1 and Rac2 GTPases and extracellular signal-regulated kinase (ERK). In H4R-expressing HEK293A cells, cystamine reduced basal and agonist-induced cyclic AMP response element reporter activity, demonstrating competitive antagonism and inverse agonism. Molecular docking supported direct binding of cystamine-but not its reduced monomer, cysteamine-to H4R. These findings identify cystamine as a redox-dependent inverse agonist of the H4R and provide a mechanistic explanation for its reported anti-inflammatory properties. Notably, cystamine generated endogenously or reformed locally from cysteamine under oxidative conditions may act on H4R in a redox-dependent and microenvironment-specific manner. Together, these insights suggest the potential for developing redox-dependent, tissue-selective H4R modulators for inflammatory diseases. This study identifies cystamine as a previously unrecognized modulator of H4R. Cystamine inhibits mast cell migration and suppresses H4R-mediated Rac-ERK signaling at concentrations far below those required to inhibit transglutaminase, and it exhibits inverse agonist activity. Docking simulations show that cystamine, but not reduced cysteamine, engages the receptor's orthosteric site, revealing a redox-dependent difference in receptor interaction.
PIEZO1 channel mechanosensing in hepatobiliary physiology and disease.
Konstantinou C, Patel SK, Lalor P … +9 more , Moore JB, Roberts LD, Endesh N, Wah TM, Samson A, Hakeem AR, Prasad KR, Beech DJ, Lichtenstein L
Am J Physiol Cell Physiol · 2026 Feb · PMID 41467771 · Publisher ↗
The hepatobiliary system is constantly exposed to dynamic mechanical forces, including fluid shear stress, bile canaliculi pressure, and extracellular matrix stiffness. Although traditionally studied for its metabolic an...
The hepatobiliary system is constantly exposed to dynamic mechanical forces, including fluid shear stress, bile canaliculi pressure, and extracellular matrix stiffness. Although traditionally studied for its metabolic and detoxifying functions, it is now increasingly recognized as a mechanosensitive organ. This review focuses on PIEZO1 mechanically gated ion channels that transduce physical cues into calcium-dependent signaling events. PIEZO2, the only other PIEZO isoform, is not known to be relevant in the hepatobiliary system. We examine the current knowledge on PIEZO1 in liver physiology, highlighting its roles in liver sinusoidal endothelial cells, hepatocytes, and macrophages. In health, PIEZO1 regulates key processes such as bile acid synthesis (through nitric oxide-mediated suppression of ), bile flow, antioxidant defense, and iron homeostasis. In disease, PIEZO1 activity is linked to pathological processes such as inflammation, fibrosis, and angiogenesis in the context of cirrhosis and hepatocellular carcinoma. We discuss the idea that the liver alternates between two functional states depending on portal vein flow: a high-flow state favoring detoxification and metabolism, and a low-flow state that prioritizes bile acid production. Understanding how PIEZO1 contributes to these transitions offers new insights into liver's ability to adapt its function and metabolism. Further research on hepatobiliary PIEZO1 will advance the understanding of how physical exercise promotes health and opens new opportunities for enhancing liver regeneration after surgical resection and liver function in chronic diseases such as fibrosis and cirrhosis.
Plasma extracellular vesicle signatures of metabolic health and exercise response in a pilot study of older adults.
Zhang X, Kraus WE, Houmard JA … +2 more , Johnson JL, Kraus VB
Am J Physiol Cell Physiol · 2026 Feb · PMID 41467764 · Full text
Extracellular vesicles (EVs) are key mediators of intercellular communication and regulators of cellular function, yet their roles in metabolic health and exercise response are poorly understood. This pilot study analyze...
Extracellular vesicles (EVs) are key mediators of intercellular communication and regulators of cellular function, yet their roles in metabolic health and exercise response are poorly understood. This pilot study analyzed plasma from older adults ( = 20) in subgroups of the well-characterized Studies Targeting Risk Reduction Interventions through Defined Exercise (STRRIDE) study to evaluate plasma EV biomarkers as minimally invasive biomarkers of metabolic health and exercise responsiveness. Plasma EVs comprised highly heterogeneous subpopulations defined by diverse surface markers reflecting complex cellular origins. At baseline, multiple EV biomarkers related to immune cells, skeletal muscle, and mesenchymal stem cells were associated with better indices of insulin action, including nine EV subpopulations with lower fasting insulin concentration and eight with lower Homeostatic Model Assessment for Insulin Resistance. Low-amount (∼1,300 kcal/wk), vigorous-intensity (65%-80% peak oxygen consumption) aerobic exercise increased the FABP4 EV subpopulation in older adults ( = 12). High-amount (∼2,200 kcal/wk), vigorous-intensity exercise increased 15 EV subpopulations in older adults ( = 8). These subpopulations arise from a variety of cell sources, including immune cells (primarily lymphoid cells), skeletal and cardiac muscle, erythroid cells, mesenchymal and hematopoietic stem cells. Notably, eight out of 15 high-amount exercise-induced EV subpopulations were insulin action-related (CD29, CD8, CD56, CD19, MCAD, CD73, CD105, and CD235a). The EV-based profiling platform established here is ready for validation in larger human exercise cohorts, including the full STRRIDE cohort. Specific plasma EV biomarkers related to immune subsets, skeletal muscle, and mesenchymal stem cells were associated with better indices of insulin action at baseline. High-volume, vigorous-intensity aerobic exercise increased many of these insulin action-related EV subpopulations. We developed a novel, minimally invasive platform that uses plasma EV surface markers to assess metabolic health and exercise responsiveness. This platform is ready for validation in larger human cohorts, including the full STRRIDE cohort.
Selective modulation of murine intestinal M and M muscarinic receptor expression has divergent effects on specialized epithelial cells and body weight.
Sampaio Moura N, Schledwitz A, Cheng K … +9 more , Song Y, Kwon MS, Cairns CA, Njei LP, Raufman B, Drachenberg CB, Wang JY, Ma B, Raufman JP
Am J Physiol Cell Physiol · 2026 Feb · PMID 41452458 · Full text
M and M muscarinic receptors encoded by and mediate neuronal and non-neuronal cholinergic signaling. Mice with global MR deficiency reportedly weigh less than controls, but the cell type(s) involved are unknown. As the...
M and M muscarinic receptors encoded by and mediate neuronal and non-neuronal cholinergic signaling. Mice with global MR deficiency reportedly weigh less than controls, but the cell type(s) involved are unknown. As the intestinal epithelium modulates nutrient absorption, we asked whether deleting MR and MR only from intestinal epithelial cells would alter the distribution of specialized small intestinal epithelial cells or body weight. We reviewed reports of global MR and MR deficiency and body weight, used single-cell RNA sequencing (scRNA-Seq) to assess and expression by small intestinal epithelial cells, created mice with conditional intestinal epithelial cell MR and MR deletion (CKO mice), and compared the distribution of specialized intestinal epithelial cells and body weights of CKO and control mice, and the development of enteroids. Prior weight comparisons commonly used only male mice, frequently without comparison with littermate controls. scRNA-Seq analysis of tissues from MR and MR floxed mice revealed robust and expression by enteric goblet cells. CKO mice with selective mucosal depletion of and RNA were viable, fertile, and had fewer small intestinal goblet cells than controls. MR CKO mice had more tuft cells than controls. Although female mice weighed ∼20% less than males, we detected no weight differences between MR and MR CKO and control mice; enteroids derived from these mice developed at the same pace. Intestinal epithelial cell MR and MR deficiency impacts the distribution of specialized intestinal epithelial cells but not murine body weight. Small intestinal goblet cells robustly express both and ; mucosal immune cells express primarily . Mice with intestinal epithelial cell (IEC) /MR deletion have fewer small intestinal goblet cells but more tuft cells. The increase in tuft cells, which produce acetylcholine, may represent a feedback mechanism to compensate for reduced muscarinic receptor (MR) expression. IEC-selective deletion of MRs does not impact murine weight or enteroid development, suggesting that MRs beyond the intestinal epithelium regulate weight.
β-Hydroxy-β-methylbutyrate enhances fast-twitch muscle and mitochondrial function, histopathology and mTORC1 signalling in the dystrophic mouse.
Giourmas N, Lalunio H, Wu C … +4 more , Bagaric R, Calzoni M, Goodman CA, Hayes A
Am J Physiol Cell Physiol · 2026 Feb · PMID 41442143 · Publisher ↗
Duchenne muscular dystrophy (DMD) is one of the most severe forms of inheritable muscular dystrophies, caused by a genetic mutation resulting in the loss of dystrophin. Dystrophin loss initiates a cascade of negative mec...
Duchenne muscular dystrophy (DMD) is one of the most severe forms of inheritable muscular dystrophies, caused by a genetic mutation resulting in the loss of dystrophin. Dystrophin loss initiates a cascade of negative mechanistic changes in skeletal muscle, such as disrupted protein homeostasis and mitochondrial dysfunction. Recent evidence suggests the leucine metabolite, β-hydroxy-β-methylbutyrate (HMB), may improve physical function in DMD boys and improve aspects of the dystrophic phenotype in preclinical mice. HMB has been shown to modulate protein turnover and mitochondrial function, both of which are dysregulated in DMD. Therefore, this study examined the effect of 3-wk of HMB supplementation (0.75 mg/g/day via drinking water), starting at 3-wk of age in mice. HMB-treated mice exhibited increased full-body grip strength and holding impulse, compared with controls. HMB treatment also increased normalized muscle mass of the fast-twitch extensor digitorum longus (EDL) muscle, which coincided with increased average fiber size and improved absolute/specific in vitro force production. Moreover, HMB-treated EDL muscles displayed increased mitochondrial complex II succinate dehydrogenase activity, alongside upregulated markers of mammalian target of rapamycin complex 1 (mTORC1) signalling (p70S6K1 and 4EBP1 phosphorylation), suggestive of increased protein synthesis. Finally, muscle fibers isolated from HMB-treated mice showed improved mitochondrial efficiency that was associated with increased maximal respiration, spare respiratory capacity, and ATP synthesis. This study is the first to show HMB-induced improvements on in vitro and in vivo measures of skeletal muscle force production that are coupled with improved mitochondrial function, suggesting that HMB may be a viable treatment option for DMD. This is the first study to examine the effect of HMB in 3-wk-old mice undergoing extensive muscle damage and regeneration both in vivo and in vitro. HMB treatment increased voluntary grip strength and holding impulse, while elevating force production of isolated EDL muscles, which were associated with improved muscle mass, muscle fiber size, and succinate dehydrogenase activity. Finally, these improvements coincided with increased markers of mTORC1 signalling, mitochondrial respiration, and ATP production.
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